Project Summary/Abstract Led by groundbreaking studies in invertebrate models, our understanding of the mechanisms of aging has grown exponentially in the past 25 years. Despite this growth, there are many aspects of the genetic and molecular mechanisms of aging that are still not well understood. One of these mechanisms is the ability of small subsets of cells (frequently neurons) to modulate the aging process cell non-autonomously. Recently, multiple high-impact publications have identified individual genes and neurons that initiate signaling pathways and eventually modify the physiology of peripheral tissues to benefit health and longevity. These studies provide substantial evidence that cell non-autonomous control of aging is common to multiple longevity pathways, but they lack in detail as to the specific signals, receptors, and neural circuits involved. Our preliminary data identify a new cell non-autonomous longevity pathway, led by the transcription factor necessary to respond to low oxygen environments, the hypoxia-inducible factor (hif-1). We further find that stabilization of HIF-1 in neurons, through either genetic or environmental approaches, leads to induction of an intestinal protein, flavin-containing monooxygenase-2 (fmo-2), that is both necessary and sufficient to improve healthspan, stress resistance, and longevity. We observe that induction of fmo-2 and extension of lifespan by HIF-1 stabilization each depend on the presence of the serotonin producing enzyme tph-1 and the serotonin receptor ser-7. This project will map core neural components of the cell non-autonomous pathway initiated by stabilization of neuronal HIF-1 that eventually leads to intestinal fmo-2 induction and extension of lifespan. Aim 1 will focus on the initiation of the response, including the identity of the neurons and the timing and mechanism of HIF-1's promotion of physiological changes cell non-autonomously. The results will establish where and how a small subset of neurons initiates a broad response to low oxygen. The second aim focuses on the neuron expressing ser-7, a highly conserved serotonin receptor that propagates the HIF-1-mediated signal. The third aim will focus on the neural circuit downstream of HIF-1, identifying key propagating and integrating cells and core signals both unique to this pathway and shared by other cell non-autonomous networks. The results will define a neural circuit led by HIF-1 and utilizing serotonin that may partially overlap with other longevity pathways. The resulting data are crucial to our understanding of defined networks that control physiology and the rate of aging, and will likely lead to future studies designed to mimic signals in these networks. Together, these aims will act independently and synergistically to provide an understanding of a major signaling network that modifies aging. Our ultimate goal is to exploit this knowledge of control mechanisms of aging to develop approaches that promote human health.